Direct compression vehicles

ABSTRACT

Tablets are formed directly without granulation or slugging from a mixture of an active material, such as a therapeutic material, and as a direct compression vehicle, a dry, freeflowing, granular sugar composition comprising generally spherical, porous, firm agglomerates of 100 parts of solid sugar in from about 0.1 to about 30 parts of a cementum or matrix. The sugar agglomerates are obtained by: 1. Spraying a particulate solid sugar with an aqueous solution of binder; 2. Providing the resulting mixture with sufficient high intensity agitation to uniformly intermingle the sugar and binder and to build up agglomerates of a desired size; 3. &#39;&#39;&#39;&#39;Snowballing&#39;&#39;&#39;&#39; the agglomerates to impart a general spherical shape thereto and to firm or densify the agglomerate; 4. Drying; and if necessary, 5. Separating over- and undersized agglomerates. The mixture may also contain additives such as colors, flavorants and the like.

United States Patent [72] Inventors John P. Troy Hicksville; AnthonyMonti, lrvington; Frank J. Lynch, Staten Island, all of N.Y.; Charles B.Broeg,

Short Hills, N .J.

[2]] Appl. No. 820,285

[22] Filed Apr. 29, 1969 [45] Patented Dec. 14, 1971 [73] AssigneeSuCrest Corporation New York, N.Y.

[54] DIRECT COMPRESSION VEHICLES 10 Claims, No Drawings [52] US. Cl127/29, 8/79, 99/26, 99/134 R, 99/141 A, 127/63,

Primary Examiner-Joseph Scovronek Assixlan! Examiner-Sidney MarantzAll0rneyKenyon & Kenyon Reilly Carr 81. Chapin ABSTRACT: Tablets areformed directly without granulation or slugging from a mixture of anactive material, such as a therapeutic material, and as a directcompression vehicle, a dry, free-flowing, granular sugar compositioncomprising generally spherical, porous, firm agglomerates of 100 partsof solid sugar in from about 0.1 to about 30 parts of a cementum ormatrix. The sugar agglomerates are obtained by:

l. Spraying a particulate solid sugar with an aqueous solution ofbinder;

2. Providing the resulting mixture with sufficient high intensityagitation to uniformly intermingle the sugar and binder and to build upagglomerates ofa desired size;

3. Snowballing" the agglomerates to impart a general spherical shapethereto and to firm or densify the agglomerate;

4. Drying; and if necessary,

5. Separating overand undersized agglomerates. The mix ture may alsocontain additives such as colors, flavorants and the like.

DIRECT COMPRESSION VEHICLES This invention relates to tablets comprisingan active material and a direct compression vehicle. More particularly,this invention is concerned with tablets comprising an active materialand a direct compression vehicle, which are formed from a mixturethereof without prior granulation or slugging.

There are two general methods for forming tablets, i.e., compression ofa dry particulate material and trituration, or molding of a moistmaterial, of which the first technique is by far the most frequentlyemployed. The compression technique may be further subdivided into threemajor categories, viz direct compression, wet granulation and drygranulation. The direct compression technique is the most desirable, inthat it employs the fewest steps and, in the case of the production oftablets containing sensitive or unstable actives, such as certainpharmaceuticals, minimizes the exposure to water or other conditionstending to adversely affect stability of the active. Unfortunately,however, it has been found that the direct compression technique is oflimited applicability.

First, most active materials possess poor compression properties, andthus are unsuitable for this technique. In addition, many actives arerequired in such small amounts per unit dosage form that directcompression of the active alone is impractical, if not impossible. As aresult, the active must be admixed with a direct compression vehicle,i.e., an inert composition which is compatible with the active and hasgood compressibility and binding action. In addition, the directcompression vehicle should have good flowability, good stability undernormal ambient conditions, no adverse effect on tablet disintegrationtime, the ability to produce good tablet surfaces, and low cost.

To date, however, no material has been found which satisfies all ofthese criteria. For example, of the most popular of such compressionvehicles, spray-dried lactose possesses poor stability and discolors onstoring, dicalcium phosphate provides tablets having poor strength, andmicrocrystalline cellulose is expensive.

One of the principal objects of this invention is to provide a directcompression vehicle.

Another object of the invention is to provide an improved tablet as thefinal product as a result of the more effective quality control madepossible by eliminating variables in the manufacturing process.

Another object of the invention is to permit the use of a wide varietyof materials in the manufacture of tablets.

Another object of the invention is to provide a novel method ofmanufacturing tablets in which the complicated steps inherent in agranulation process are avoided.

Other objects and advantages in this invention will be apparent to thoseskilled in the art of tablet manufacture when reviewing thespecification and claims of this invention.

It has been discovered in accordance with this invention that certainsugar agglomerates are well suited for use as a direct compressionvehicle for the production of tablets. This material comprises generallyspherical, firm, porous agglomerates of sugar particles in a cementum ormatrix. The agglomerates are dry (from about 0.1 to about 3 percentmoisture), free-flowing particles having particle size within the rangeof from about 325 to about 12 mesh. Tablets formed using such sugaragglomerates as the direct compression vehicle are uniform, possess goodphysical properties, do not discolor on aging, and readily dissolve inaqueous media.

These sugar agglomerates are obtained by:

l. Spraying a particulate solid sugar with an aqueous solution ofbinder;

2. Providing the resulting mixture with sufficient high intensityagitation to uniformly intermingle the sugar and binder and to build upagglomerates of a desired size;

3. Snowballing the agglomerates to impart a general spherical shapethereto and to firm or densify the agglomerate;

4. Drying; and if necessary,

5. Separating overand undersized agglomerates.

The particulate sugar can be a mono-, dior tri-saccharide, such asarabinose, xylose, ribose, fructose, mannose, galactose, glucose,sucrose, maltose, lactose and the like, including mixtures of two ormore of such sugars, with sucrose being preferred. The particulate sugarcan be obtained synthetically, or it can be a refined natural product,such as corn syrup solids, molasses solids, honey solids, maple syrupsolids and the like. The particle size of the sugar is not narrowlycritical so long as it is small enough to permit formation ofagglomerates of the desired size. For most purposes, ordinary 6X poweredsugar, of which most to 97 percent) passes through a ZOO-mesh screen, issuitable. if the agglomerate is to be employed in the production of achewable tablet, however, it is desirable that more finely divided sugarbe used to avoid grittiness."For this use, the sugar should havesubstantially no particles, i.e., not more than 1 percent, having sizesgreater than about 40 microns, and at least 50 percent of the particlesshould have sizes below about 25 microns. Preferred are sugars having anaverage particle size of about 15 microns.

The second component which is employed to form the agglomerate is anoncrystallizing aqueous solution of a polyhydroxy compound as a binder.Illustrative polyhydroxy compounds include propylene glycol, glycerol,erythritol, arabitol, xylitol, adonitol, mannitol, dulcitol, sorbitol,sugars, such as arabinose, xylose, ribose, glucose, mannose, fructose,sucrose, maltose and lactose, dextrin and the like, with polyols of theformula HOCH (CHOH),CH OH, wherein x is l to 4, and sugars beingpreferred. Propylene glycol, glycerol, mannitol, sorbitol, glucose,fructose and invert sugar are of particular interest, with invert sugarbeing most preferred. The aqueous binder composition can be a solutionof a pure compound, or can comprise two or most polyhydroxy binders. Theaqueous medium can be obtained synthetically, or it can be a refinednatural product, such as corn syrup, molasses, honey, maple syrup andthe like. lnvert syrup is preferred.

The concentration of binder in the aqueous medium is not narrowlycritical provided that it is not so high as to cause crystallization orprovide solutions so viscous as to prevent spraying and intimateintermingling and uniform distribution of binder and solids. Thus, theconcentration will depend upon the solubility of the binder. Forexample, glucose ordinarily cannot be employed in amounts greater thanabout 48 percent, whereas propylene glycol, glycerol, mannitol andsorbitol can be present in amounts up to about 80 percent. When invertsugar is the binder, concentrations of from about 50 to about 80 percentare employed, with concentrations of from about 70 to about 75 percentbeing preferred. Other than this, the amount of water in the aqueousmedium should be so correlated with the desired ratio of binder to sugarthat agglomeration occurs. Thus the amount of water should beinsufficient to form a paste and yet sufficient to minimize the presenceof powder, or unagglomerated sugar. In general, it has been found thatthe mixture of particulate sugar and aqueous binder medium shouldcontain from about 2 to about 6 percent water, with amounts of about 4percent water being preferred.

The initial contact of the solids and liquids is effected by sprayingthe aqueous medium onto the dry solids at a rate such that there isemployed from about 0.1 to about 30 parts of binding agent per 100 partsof solid.

The mixing is ordinarily conducted at about room temperature (6575 F.).Higher and lower temperatures can be employed, if desired, provided theproperties of the aqueous medium and the agglomerate product are notadversely affected. In particular, the temperature of the aqueous mediummay be varied to achieve a desired viscosity for spraying. However, ifthe temperature is too low, e.g., below about 50 F., the aqueous mediumis ordinarily too viscous to be easily sprayed; and if the temperatureis too high, e.g., above about 200 F., water may evaporate too rapidlyto permit adequate control of the characteristics of the bindingsolution. In addition, the use of elevated temperatures duringprocessing tends to result in a discolored product, and also may causedissolution of the dry ingredient and thus adversely affect particlesize and quality.

Simultaneously with the spraying, the mixture is agitated to thoroughlyintermingle the solid sugar and the aqueous binder medium and to effectagglomeration. This requires high intensity mixing, such as is obtainedwith a Patterson-Kelley blender or a Lodige mixer.

Agitation is continued until agglomerates of the desired size areformed, and ordinarily for a time sufficient to form agglomerates aboutabout 325 mesh, but insufficient to form significant amounts ofagglomerates larger than about l2 mesh. The size of the agglomerate isalso affected by the ratio of aqueous binder to particulate sugar, withlarger agglomerates being formed when a greater proportion of liquidmedium is present.

The agglomerates typically have a narrow size distribution. That is,high yields, normally 80 percent or more, of the agglomerates fallwithin a few screen sizes. For example, when operating to produce a 20-to 80-mesh agglomerate, at least 80 percent, and in some instances 90percent or more, of the agglomerated product will fall within thisrange.

Simultaneously with and/or subsequent to agglomeration, the agglomeratesare snowballed, i.e., subjected to a tumbling or rolling operation, toimpart a general spherical shape thereto. In addition, the agglomeratesare firmed or densified whereby the bulk density is increased by about50-100 percent over that of the dry particulate sugar, and normally isin the range of from about 30 to about 50 pounds per cubic foot.

The apparatus employed can be any suitable equipment which will achievethe desired results. A particularly preferred apparatus is thePatterson-Kelley blender, which performs all three operations of mixing,agglomerating and snowballing.

Finally, and when necessary, the agglomerates are dried to a moisturecontent of less than about 3 percent, and preferably less than about 1.5percent. Although complete drying is theoretically possible, themoisture content of the product need not be less than about 0.! to 0.2percent. The temperature at which drying occurs is not narrowly criticalin all cases, but ordinarily the temperature of the agglomerate shouldnot exceed about 140 F. To achieve such drying, the product ispreferably contacted with hot air at a temperature not exceeding 190 F.A preferred drying technique is the use of a fluid bed dryer. In thismanner, very fine particles, i.e., dust, are separated from the product.

If desired, the dried product may be screened. to remove oversized andundersized particles. Oversized particles are discarded or can bereduced to smaller size. Undersized particles can be recycled.

The resulting agglomerate is admixed with the active material and theresulting mixture compressed without granulation or slugging to form atablet. The amount of the agglomerate obviously will depend upon theproperties of the active and any other additives which are to beincorporatedinto the finished tablet, for it is well known that thecompactibility of tablet compounds and mixtures are subject to widevariation. in general, however, the agglomerate will comprise at leastpercent of the tabletting mixture and, therefore, at least 10 percent ofthe tablet. in most cases, however, the agglomerate will comprise fromabout 70 to about 95 percent of the tabletting mixture and the tablet.

By the term active material is meant any material intended for ingestionand having a beneficial or desirable effect on the user. Suitable activematerials include therapeutic materials, such as anesthetics,antibiotics, antitussives, vitamins, aspirin, antacids, and the like;food stufis such as cocoa, dried oats, fruit flakes, and the like;edible dyes and other food additives; and so on.

In addition to the sugar direct compression vehicle and the activematerial, there may be employed other commonly employed tablet and waferadditives such as coloring agents, flavorants, lubricants, gums and thelike. Although ordinarily not required because of the ready solubilityof the product tablet in aqueous media, disintegrants may also beemployed.

The vehicle is a free-flowing granular material and imparts improvedflow characteristics to the active material and other components of theblend, thereby assuring ease of tabletting. The blend of directcompression vehicle, active material and other additives is mixed anddirectly compressed to form a tablet employing conventional techniquesand apparatus.

The following examples are illustrative. As used throughout thisapplication, all parts and percentages are by weight unless otherwisestated.

EXAMPLE I To parts of finely pulverized sucrose is rapidly added over aperiod of 5 minutes by spraying at room temperature and while agitatingthe pulverized sugar l4 parts of an aqueous invert sugar solution (72percent total solids) in a PattersonKelley liquids-solids blender. Aftercontinuing agitation for an additional 10 minutes, the agglomeratedmaterial is screened through a vibrating l6-mesh screen and the screenedmaterial is dried to a moisture content of 1.5 percent or less. To 97parts of dry agglomerated product is added, under agitation, 1 part ofdry citric acid, 0.25 part of dry flavoring material and 1.75 part ofmagnesium stearate. The properly blended material is fed to a tablettingpress and wafers are formed from it.

EXAMPLE 2 Employing procedures similar to those described in example 1,98 parts of finely pulverized sucrose is mixed with about 6.7 parts ofan aqueous invert sugar solution (30 percent total solids). Theagglomerated material is screened through a vibrating mesh screen andthe screened material is dried to a moisture content of 1.5 percent orless.

Equal parts of the agglomerate and vitamin C are blended. This blend canbe further mixed with other dry ingredients such as minerals or othernutritionally active ingredients before being compressed into tablets.

EXAMPLE 3 Employing procedures similar to those described in example l,a blend of lOO parts of finely pulverized dextrose monohydrate issprayed with 14 parts of dextrose syrup (48 percent total solids). Theagglomerated material is screened and dried to a moisture content of 1.5percent or less.

The agglomerated material can be directly compacted after adding andblending the proper release agent (magnesium stearate). Rapidlydisintegrating ingredients can also be included in the formulation priorto tabletting.

EXAMPLE 4 Employing procedures similar to those described in example l,a blend of 90 parts of finely pulverized sucrose and 10 parts of finelycomminuted dextrose are sprayed with about 14 parts of invert syrup (72percent total solids). The agglomerated materials is screened, and driedto a moisture content of 1.5 percent or less.

Equal parts of the agglomcrate and aluminum hydroxide are blendedtogether. This blend can be further mixed with small amounts offlavoring or other dry ingredients before being compressed into acommercial antacid tablet.

EXAMPLE 5 Employing procedures similar to those described in example l,parts of finely pulverized dried molasses are sprayed with about 6.5parts of afi'mation syrup (76 percent total solids). The agglomeratedmaterial is screened and dried to a moisture content of 1.5 percent orless.

Equal parts of the agglomerate and dried ground oats are blended. Thisproduct can be further mixed with other dry ingredients such as mineralsor other nutritives. After compacting, wafers for animal feeding areobtained.

EXAMPLE 6 To 90 parts of pulverized sucrose having an average particlesize of microns, less than 1 percent thereof exceeding 40 microns, andmore than 50 percent thereof less than 25 microns in size, the saidpulverized sugar being in a Patterson- Kelley liquids-solids blender,there is rapidly added by spraying at room temperature (65 F.), andwhile agitating the pulverized sucrose, about 14 parts of an aqueousinvert sugar solution (72 Brix). A small amount of monocalcium phosphateis added to adjust the pH to 4.5-4.8 to prevent discoloration. After theaddition of the invert syrup has been completed, the blender is run forabout 2 minutes to complete the agglomeration. The total time ofoperation, i.e., spraying and agglomeration, is about 6 minutes.

The resultant agglomerated material, which contains about 3.8 percentwater, is then screened through a vibrating mesh screen. Theagglomerates coarser than 20 mesh are still relatively soft and can berubbed through an auxiliary screen and added to the first product. Thescreened material is then placed in a rotary drier and warm air at about180 F. is circulated through the drier to dry the agglomerates to awater content of 1 percent. The drier is operated so that thetemperature of the agglomerates does not rise about 140 F. The driedproduct is then further screened on an 80-mesh screen. The materialremaining on the screen is the finished product. That passing throughthe screen may be returned to the blender for reprocessing, or may beemployed as a fine particle size granular product.

This agglomerate can be blended in accordance with the following recipesand compressed.

A. CONFECTIONERY TABLETS OR WAFERS 1. Lemon Flavored ConfectioneryTablet: 100.0 pts. agglomerate 1.0 pt. citric acid, dry

0.25 pt. encapsulated lemon flavor 0.10 pt. yellow color No. 5

1.0 pt. magnesium stearate 2. Grape Flavored Tablet:

50.0 pts. agglomerate 50.0 pts. 6X powdered sugar 2.0 pts. tartaric acid0.25 pt. grape flavor 0.05 pt. grape color 0.5 pt. calcium stearate 3.Cherry Flavored Confectionery Tablet: 100.0 pts. agglomerate 2.0 pts.fumaric acid 0.2 pts. cherry flavor 0.1 pt. red color 1.0 pt. magnesiumstearate B. PHARMACEUTICAL FORMULATIONS 50.0 pts. agglomerate 37.5 pts.aluminum hydroxide 1.0 pt. magnesium stearate 100.0 pts. 25.0 pts. 5.0pts.

1 drop 2.0 pts.

agglomerate acetyl salicylic acid corn starch magnesium stearate Otheractive ingredients of use in blends with the agglomerate are: sodiumbicarbonate, acetanilid, phenacetin, and magnesium trisilicate. C.SPECIALTY PRODUCTS 1. Invertase Sugar Tablet 96.4 pts. agglomerate 3.6pts. liquid triple strength invertase (K=0.9) 1.0 pt. magnesium stearate2. Cocoa-Sugar Tablet 90.0 pts. agglomerate 10.0 pts. high fat cocoa 0.2pts. dendritic salt 1.0 pt. magnesium stearate After blending, themixture is tabletted to form a cocoasugar tablet.

3. Sugar-Synthetic Sweetener Tablet 450.0 pts. agglomerate 7.16 pts.calcium cyclamate 0.8 pts. sodium saccharin 5.0 pts. calcium stearate 4.Highly Concentrated Color Tablet 90.0 pts. agglomerate 10.0 pts. driedyellow FD&C No. 6

10.0 pts. sodium benzoate 5. Yeast Food Tablet 34.0 pts. calcium sulfate(ZH O) 23.0 pts. flour 9.0 pts. ammonium chloride 0.25 pt. potassiumbromate 17.75 pts. sodium dihydrogen phosphate 16.0 pts. salt 900.0 pts.agglomerate 10.0 pts. magnesium stearate In the foregoing examples, thedirect compression vehicle has been a spherical agglomerate. In someinstances, in which a high degree of composition uniformity is desired,the use of the agglomerate per se has been found disadvantageous. It isreadily appreciated that the ratio of invert to particulate sugarincreases with increasing agglomerate size. For example, in the case ofa product having agglomerates in the -100 mesh range, the invert contentof the ZOO-mesh size particles is substantially less than the invertcontent of the 80-mesh particles.

It has been further found that the agglomerates tend to segregateaccording to size upon handling. For example, when a 80-200 meshfraction of the agglomerates is stored in a bag, the ZOO-mesh particlestend to settle out in the bottom of the bag during handling. As a resultof the different composition and size segregation, the composition oftablets made from the agglomerates will vary depending upon whether theagglomerate is taken from the top or the bottom of the bag.

To avoid such product variations, it has been found desirable topulverize the agglomerate and then compact the pulverized agglomerate,as for example by the use of a Fitzpatrick Chilsonator, and reduce theresulting compacted sheet to particles of a desired size. If desired,the granules of compacted agglomerate may be screened to provide aproduct of more restricted size variation.

The resulting compacted agglomerate may be employed in a manneridentical to the agglomerate itself. Thus, it may be substituted for theagglomerate in any of the foregoing examples to achieve a tablet ofsubstantially identical characteristics.

What is claimed is:

1. A method for preparing tablets containing as a direct compressionvehicle a sugar composition comprising the steps of (a) forming aunifonn nongranulated mixture of an active material and a dry,free-flowing, generally spherical, porous agglomerate of parts of asolid pulverized sugar in 0.1 to about 30 parts of a matrix of apolyhydroxy compound, and (b) compressing said mixture into tablets,said agglomerate comprising at least 10 percent of said mixture, andhaving a particle size of from about 12 to about 325 mesh, a moisturecontent of from about 0.1 to about 3 percent, and having been preparedby a process including the steps of: (l) Spraying a particulate solidsugar with an aqueous solution of binder; (2) Providing the resultingmixture with sufficient high intensity agitation to uniformlyintermingle the sugar and binder and to build up agglomerates of adesired size; and (3) Snowballing the agglomerates to impart a generalspherical shape thereto and to firm or densify the agglomerate.

2. A tablet prepared in accordance with claim 1.

3 A method according to claim I, wherein said matrix is a carbohydrate.

4. A tablet prepared in accordance with claim 3.

5. A method according to claim 3, wherein said sugar is sucrose and saidcarbohydrate is invert sugar.

6. A tablet prepared in accordance with claim 5.

7. A method for preparing a direct compression vehicle comprisingcompacting a dry, free-flowing, generally spherical, porous agglomerateof I parts of a solid pulverized sugar in 0.] to 30 parts of a matrix ofa polyhydroxy compound, said agglomerate having a particle size of fromabout 12 to about 325 mesh and a moisture content of from about 0.1 toabout 3 percent, said agglomerate being prepared by a process includingthe steps of:

l. Spraying a particulate solid sugar with an aqueous solution ofbinder;

2. Providing the resulting mixture with sufficient high intensityagitation to uniformly intermingle the sugar and binder and to build upagglomerates of a desired size; and

3. Snowballing the agglomerates to impart a general spherical shapethereto and to firm or densify the agglomerate,

and thereafter comminuting said compacted agglomerate to a desiredparticle size.

8. The product of claim 7.

9. A method for preparing a tablet comprising forming a uniformadmixture of the product of claim 8 and active material, said productcomprising at least 10 percent of said mixture, and compressing themixture into tablets.

10. A tablet produced according to claim 9.

1. SPRAYING A PARTICULATE SOLID SUGAR WITH AN AQUEOUS SOLUTION OFBINDER;
 2. PROVIDING THE RESULTING MIXTURE WITH SUFFICIENT HIGHINTENSITY AGITATION TO UNIFORMLY INTERMINGLE THE SUGAR AND BINDER AND TOBUILD UP AGGLOMERATES OF A DESIRED SIZE;
 3. "SNOWBALLING" THEAGGLOMERATES TO IMPART A GENERAL SPHERICAL SHAPE THERETO AND TO FIRM ORDENSIFY THE AGGLOMERATE;
 2. A tablet prepared in accordance withclaim
 1. 2. Providing the resulting mixture with sufficient highintensity agitation to uniformly intermingle the sugar and binder and tobuild up agglomerates of a desired size; and
 3. ''''Snowballing'''' theagglomerates to impart a general spherical shape thereto and to firm ordensify the agglomerate, and thereafter comminuting said compactedagglomerate to a desired particle size.
 3. A method according to claim1, wherein said matrix is a carbohydrate.
 4. A tablet prepared inaccordance with claim
 3. 4. DRYING; AND IF NECESSARY,
 5. SEPARATINGOVER-AND UNDERSIZED AGGLOMERATES. THE MIXTURE MAY ALSO CONTAIN ADDITIVESSUCH AS COLORS, FLAVORANTS AND THE LIKE.
 5. A method according to claim3, wherein said sugar is sucrose and said carbohydrate is invert sugar.6. A tablet prepared in accordance with claim
 5. 7. A method forpreparing a direct compression vehicle comprising compacting a dry,free-flowing, generally spherical, porous agglomerate of 100 parts of asolid pulverized sugar in 0.1 to 30 parts of a matrix of a polyhydroxycompound, said agglomerate having a particle size of from about 12 toabout 325 mesh and a moisture content of from about 0.1 to about 3percent, said agglomerate being prepared by a process including thesteps of:
 8. The product of claim
 7. 9. A method for preparing a tabletcomprising forming a uniform admixture of the product of claim 8 and anactive material, said product comprising at least 10 percent of saidmixture, and compressing the mixture into tablets.
 10. A tablet producedaccording to claim 9.